The present invention relates to methods and devices for the agglomeration of finely divided powders, e.g., powdered medicaments for inhalation therapy.
Finely divided powders, i.e., powders having a very small particle size, typically less than 5-10 xcexcm, are commonly used in inhalation therapy. In this application, the particle size of the powder is of the utmost importance. The diameter of the particles to be inhaled must be less than 10 xcexcm or the particles will not adequately penetrate the bronchial area of the lungs. It is also very important in inhalation therapy that a precisely controlled dosage be administered. The inhaled route of administration enables the dose to be delivered directly to the airways, and thus allows a very small dosage to be given, minimizing side effects, but also making precise metering of the powder dosage crucial.
Particle size control and precise metering are often made problematic by the flow properties of finely divided powders. Most finely divided powders are light, dusty and fluffy. Further, the van der Waals forces of the particles exceed the force of gravity, causing the particles to be cohesive. This combination of properties make the powder flow poorly, complicating handling, processing and storage, and making it difficult to meter and dispense a precise dosage of the powder. The particles also tend to adhere to each other during storage and handling, forming agglomerates. Because these agglomerates are made up of a number of primary particles, they typically have diameters in excess of 10 xcexcm. Accordingly, if the agglomerates do not break down into primary particles during inhalation the powder dosage will not properly penetrate the bronchial area. Also, if agglomeration is not controlled, random sized agglomerates may result, making precise metering of the powder difficult.
The flow properties of the powder can be improved by controlled agglomeration of the powder, e.g., by vibration, agitation or rolling of the powder with or without a binder. However, the agglomerates must have sufficiently low internal coherence so that they readily break into primary particles during inhalation in an inhalation device.
Methods of controlled agglomeration are known in the art. For example, Claussen and Petrow (Journal of Materials Technology, vol 4(3), pp. 148-156 (1973)) describe a method of agglomeration by tumbling in a cylinder tilted at an angle to the horizontal axis of rotation. U.S. Pat. No. 5,143,126 describes a vibratory conveyor for forming flowable agglomerates from previously poorly flowable fine-grained powder by subjecting the powder to a mechanical vibration step prior to transport and metering. GB 1,569,611 describes a process for agglomeration of a drug into soft pellets, using a binder to produce a paste which is extruded through a sieve to create agglomerates. GB 2,187,952 describes a method of agglomeration by kneading a crystalline powder as it is conveyed by conveying screws through an extruder.
The invention features a method of treating a finely divided powder that includes forcing the powder through a sieve to form agglomerates, and spheronizing the agglomerates. This process has been found to produce agglomerates having excellent handling properties, which have sufficient strength to withstand packaging and storage, but which are sufficiently soft so that they will easily break down into primary particles when they are expelled from an inhaler during inhalation therapy. In preferred embodiments, the agglomerates have a hardness of less than 100 mN, more preferably less than 20 mN, and most preferably between 0.5 and 20 mN as measured by a MHT-4 Microhardness tester (A. Paar, Austria).
The method is particularly suitable for use with finely divided powdered medicaments having a particle size of less than about 10 xcexcm. In preferred aspects, the medicament is selected from the group consisting of terbutaline, budesonide and lactose. Typically, the agglomerates after the final step of the method have a diameter of less than about 2 mm, a bulk density of from about 0.2 to 0.4 g/ml, and a surface area of from about 2-20 m2/g.
Preferably, the sieve comprises a U-shaped trough. In other embodiments, the sieve comprises a flat sieve having apertures greater than 0.5 mm, or a conical sieve.
In preferred aspects, the spheronization step comprises placing the agglomerates in a tilted container and rotating the container to tumble the agglomerates. Preferably, the container is a granulating pan, is provided with at least one scraper, and is tilted at an angle of from 10xc2x0-80xc2x0 from the vertical. More preferably, the container is tilted at an angle of from 30xc2x0-60xc2x0 from the vertical. Preferably, the spheronization step is performed for about 2 to 20 minutes and the container is rotated at a periphery speed of from about 0.5 to 1.0 m/s.
Preferably, the method further includes sizing the agglomerates by passing the agglomerates through a sieve. This sizing may take place after agglomeration, after spheronization, or both. Where the agglomerates are sized after spheronization, a subsequent spheronization step may be performed after this sizing step.
In another aspect, the method further includes metering a predetermined amount of the spheronized agglomerates into a breath actuated dry powder inhaler provided with means for deagglomerating the agglomerates during inhalation. In this aspect, the method may further include the step of actuating the inhaler, causing the agglomerates to be deagglomerated into primary particles by the means for deagglomerating. Other features and advantages of the invention will be apparent from the following description of a presently preferred embodiment and from the claims.